Compositions including antibiotics and methods for using same

ABSTRACT

Compositions including a quinolone component, such as ofloxacin, having fungistatic activity in the compositions, present in an amount effective as an antibiotic when the composition is placed in a mammalian eye, a NSAID component present in an amount to reduce inflammation or pain when the composition is placed in the eye, and a carrier component in an amount effective to act as a carrier for the quinolone component and NSAID component are provided. Methods of using the present compositions, for example, to resolve microbial infections and/or to reduce inflammation and/or pain in a mammalian eye are included within the scope of the present invention. Methods for treating corneal injuries are also included. In addition, methods for treating ocular infections, for example, corneal infections, are included.

RELATED APPLICATION

This application is a continuation-in-part of co-pending U.S. patentapplication Ser. No. 10/236,712, filed Sep. 6, 2002, which is acontinuation of U.S. patent application Ser. No. 09/624,129, filed Jul.14, 2000, which is a continuation-in-part of U.S. patent applicationSer. No. 09/364,334 filed Jul. 30, 1999, and U.S. patent applicationSer. No. 09/365,291, filed Jul. 30, 1999, the disclosure of each ofwhich is hereby incorporated in its entirety herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to compositions including antibiotics andto methods for using such compositions. More particularly, the inventionrelates to compositions including antibiotics which have addedprotection against fungal contamination, which reduce inflammation orpain and/or which are useful in the treatment of corneal ulcers.

Various antibiotic components have been used in ocular applications, forexample, to control or manage or prevent ocular infections and the like.Moreover, antibiotic components, such as tobramycin have been suggestedfor use in combination with other materials, such as ophthalmicallyacceptable non-steroidal anti-inflammatory drugs or NSAIDs. See, forexample, Fu et al. U.S. Pat. No. 5,414,011, the disclosure of which isincorporated in its entirety herein by reference. Quinolones, such asofloxacin, have been used in compositions for treating ocularinfections. These antibiotic compositions include one or more additionalcomponents which act as preservatives, for example, benzalkoniumchloride (BAK) or organomercurials.

Antibiotic compositions, even with preservatives, have been susceptibleto microbial, for example, fungal, contamination. In addition,preservatives tend to cause irritation, allergic reactions, and/or otherdetrimental side effects when the preserved composition is administeredto a patient.

Thus, it would be advantageous to provide antibiotic compositions, andmethods for using such compositions, which have added protection againstmicrobial contamination and/or which include relatively reducedconcentrations of preservatives.

Corneal injuries, such as corneal ulcers and other corneal conditionswhich are infected or if left untreated are likely to become infected,are quite painful and sometimes require lengthy periods of time to heal.It would be advantageous to provide compositions and methods effectiveto reduce the pain of these corneal injuries, for example, while suchinjuries are healing.

SUMMARY OF THE INVENTION

New antibiotic compositions, for example, for use in mammalian eyes,preferably human eyes, and methods for using such compositions have beendiscovered. By administering present compositions to humans or animals,for example, to the eyes of humans or animals, desired therapeuticeffects are provided, such as the prevention, control or management orsubstantial elimination of ocular microbial infections, reductions ininflammation and/or pain, reductions in pain caused by corneal injuriesand the like.

The present compositions preferably have added protection againstmicrobial, for example, fungal contamination. This feature providesadded assurance to the user that the present compositions are free ofdetrimental microbial contamination. This feature may allow reducedconcentrations of preservatives to be included in the presentcompositions, thereby advantageously reducing detrimental side effectscaused by such preservatives when the compositions are administered topatients. The present compositions can be easily produced, for example,using conventional techniques and can be conveniently used, for example,employing conventional methods of administration.

In accordance with one aspect of the invention, the compositionscomprise a quinolone component, a NSAID component and a carriercomponent. The quinolone component is present in an amount effective asa antibiotic when the composition is placed in a mammalian eye. In oneuseful embodiment, the quinolone component in the composition hasfungistatic activity. That is, the quinolone components in the presentcompositions have sufficient anti-fungal properties or activity tosubstantially prevent increases in populations of fungi in suchcompositions. In effect, the present quinolone components act aseffective preservatives against fungal growth or contamination in thepresent compositions. The fungistatic activity of the presently usefulquinolone components in the present compositions provide benefits, forexample, as described elsewhere herein, which are surprising andsubstantial. The NSAID component is present in an amount effective toreduce at least one of inflammation and pain when the composition isplaced in a mammalian eye. The carrier component is present in an amounteffective to act as a carrier for the quinolone component and the NSAIDcomponent in the composition, and preferably is ophthalmicallyacceptable.

The present compositions preferably include a quinolone component whichis halogenated, more preferably fluorinated. Very useful compositionsand results are obtained when the quinolone component is an ofloxacincomponent.

Although any NSAID component may be used, the NSAID components includedin the present compositions preferably are carboxylic (—COOH)group-containing NSAID components. More preferably, the NSAID componentis a pyrrolo pyrrole component, still more preferably a ketorolaccomponent. In another preferred embodiment, the NSAID component is aphenylacetate. In a particularly preferred embodiment the compound is abenzoyl phenylacetate such as 2-amino-3-(−4-bromobenzoyl) phenylacetatesesquihydrate, having a generic name of bromfenac. See Walsh et al., J.Med. Chem. 27:1379 (1984) and U.S. Pat. No. 4,683,242, both of which arehereby incorporated by reference herein in their entirety.

The present carrier components may contain one or more pharmaceuticallyor ophthalmically acceptable ingredients, for example, tonicity adjustercomponents, buffer components, viscosity components, lubricatingcomponents, surfactant components, preservative components and the like,conventionally used, for example, in ophthalmic formulations.Preferably, the compositions have pH's in the physiological range ofhuman beings, for example, in the range of about 4 to about 8.5.

The present compositions may be in any form suitable for effectiveadministration to the human or animal to be treated. Preferably, thecompositions are present in a form selected from aqueous solutions,suspensions, gels, ointments solids and the like which are veryeffective for ocular administration. The carrier component mayconveniently be selected and/or compounded to provide the composition inthe form desired.

In a particularly advantageous embodiment embodiment, the formulationsof the present invention are in the form of “self-preserved” ophthalmicformulations, such as ophthalmic solutions. In a particularly preferredembodiment, the formulations are packaged in the form of a unit dose,which is pre-sterilized, such as by radiation or other effective meansof sterilization without degrading the solutes, and packaged in unitdosage forms for single use.

In both single and multiple use dosage forms the ability of the presentcompositions to maintain suffficent preservative activity during storageand after opening the package is an advantage of the quinolonecomponent's useful antifungal and bacteriocidal and/or bacteriostaticproperties.

Methods of using these compositions are included in the scope of thepresent invention. Such methods comprise administering to a human oranimal, preferably to a mammalian eye, a therapeutically effectiveamounts of the compositions as described herein. Such methods provideone or more benefits to the human or animal treated in accordance withthe present methods. For example, such benefits include prevention,control or management of microbial infections, and reduction ininflammation and/or pain.

In another aspect of the present invention, methods for treating cornealinjuries are provided. As used herein, the term “corneal injury” refersto an injury of the cornea which is infected by harmful and/or unwantedmicroorganism or which, if left untreated is likely to become soinfected, for example, before this injury heals. A corneal ulcer is anexample of a corneal injury. Such methods comprise administering to amammalian eye having a corneal injury a therapeutically effective amountof a composition comprising a quinolone component in an amount effectiveas an antibiotic in the mammalian eye and a NSAID component in an amounteffective, in combination with the quinolone component, to provide areduction in pain caused by the corneal injury. Such reduction in pain,together with the antibiotic effectiveness of the presently usefulcompositions, reduces the discomfort to the patient resulting from thecorneal injury and facilitates or promotes the healing of the injury.The present useful compositions preferably include a carrier componentin an amount effective to act as a carrier for the quinolone componentand the NSAID component in the presently useful composition.

In another aspect of the present invention, methods for treating ocularinfections, such as corneal infections and the like, are provided. Suchmethods comprise administering to a mammalian eye having an infectioncaused by one or more microbes or pathogens a therapeutically effectiveamount of a composition comprising a quinolone component in an amounteffective as an antibiotic in the mammalian eye and an effective amountof a NSAID component. In one embodiment, the NSAID component is presentin an amount effective to reduce the time needed to eliminate theinfection relative to identically administering a similar compositionwithout the NSAID component. In a particularly preferred embodiment theNSAID is bromfenac. The administering step preferably is effective to atleast inhibit the offending microbe(s) or pathogen(s) from adhering to asurface of the mammalian eye and/or to inhibit colonization of theoffending microbe(s) or pathogen(s) in the mammalian eye.

Any and all features described herein and combinations of such featuresare included within the scope of the present invention provided that thefeatures of any such combination are not mutually inconsistent.

These and other aspects and advantages of the present invention are inthe following detailed description and Examples and claims.

DETAILED DESCRIPTION

The present compositions comprise quinolone components, NSAID componentsand carrier components.

Preferably, the present quinolone components exhibit fungistaticproperties in the present compositions. That is, the quinolonecomponents in the present compositions preferably are effective topreserve the present compositions against population growth of fungi,such as C. albicans and A. niger.

The fungistatic activity or properties of the present quinolonecomponents provide added protection against microbial, for example,fungal, contamination of the present compositions. Such fungistaticactivity can result in reducing the concentration of added preservativecomponents in the present compositions, thereby reducing the risk ofirritation and/or other uncomfortable side effects caused by thepresence of such added preservatives. Even if the present compositionsare substantially free of added preservative components, it has beenfound that many of the present compositions have sufficient preservativeefficacy to meet or exceed the standards of the United StatesPreservative Efficacy Test (USPET).

The present compositions include quinolone components. A number of suchquinolone components are known and have been used for many years inantibiotic applications. For example, nalidixic acid has been availablefor the treatment of urinary tract infections. The useful quinolonecomponents preferably are four-quinolones that contain a carboxylicmoiety in the three position of the basic structure shown below:

in which R₁, R₆ and R₇ are each optionally substituted C₁₋₁₀ linear,branched, or cyclical alkyl or heteroalkyl, halide, or an oxo group andwherein X is optionally substituted C, N, or C₁₋₁₀ linear, branched, orcyclical alkyl or heteroalkyl.

The present quinolone components preferably are halogenated. Forexample, a chlorinated quinolone component, such as9-chloro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyridol[1,2,3-de][1,4]benzozaxine-6carboxylic acid may be used.

More preferably, the present quinolone components are fluorinated.Examples of such useful fluorinated quinolones include norfloxacin,moxifloxacin, ciprofloxacin and ofloxacin. Such fluorinated quinolonecomponents are highly effective against a range of bacteria and areuseful in treating various microbial infections in the mammalian eye.Prior ofloxacin-containing compositions including such quinolone usedfor this purpose include additional preservatives, for example, BAK.

It has been found that the present quinolone components, such asofloxacin, have sufficient fungistatic activity to be useful in thepresent compositions to act as a preservative against fungalcontamination.

The present compositions include an antibiotically effective amount ofthe quinolone component. Such amounts may vary over a relatively broadrange depending, for example, on the specific form of the compositionbeing used, the specific quinolone component being used, the specificapplication for the composition, the frequency of use of the compositionand the like factors. In many situations, the present compositions mayinclude a quinolone component in an amount in a range of about 0.03%(w/v) or less to about 3% (w/v) or more. Preferably, the presentcompositions include the quinolone component in an amount in the rangeof about 0.15% (w/v) to about 0.5% (w/v) or about 1.1% (w/v).

The quinolone component may be any quinolone derivative which isacceptable or suitable for administration to the eye and has at least aportion, preferably a major portion or at least about 50% of theantibiotic effectiveness of the basic quinolone in the presentcomposition in the mammalian eye. The present quinolone component may beselected from the quinolone itself or quinolone hydrates orophthalmically acceptable salts of such quinolones, for example,including acid addition salts such as hydrochlorides, maleates, pamoatesand the like, and alkali metal salts such as sodium and potassium salts,and mixtures thereof and the like.

The present compositions include a NSAID component in an amounteffective to reduce inflammation and/or pain when the compositions areadministered to a mammalian eye, for example, to prevent or treatdiseases which are either caused by, associated with or accompanied byinflammatory processes and/or pain, including, among others, glaucoma,cystoid macular edema, uveitis, diabetic retinopathy and conjunctivitis,or any trauma caused by eye surgery or eye injury.

The NSAID component may or may not include a carboxylic (—COOH) group ormoiety, or a carboxylic derived group or moiety. In one embodiment, theNSAID component inhibits the cyclo-oxygenase enzyme, which has two (2)isoforms, referred to as COX-1 and COX-2. Many of the well known NSAIDcomponents are basiclaly non-selective COX inhibitors. NSAID componentswhich are selective COX-2 inhibitors are also known. Both types of NSAIDcomponents, that is both non-selective COX inhibitors and selectiveCOX-2 inhibitors are useful in accordance with the present invention.NSAID components may have prostaglandin synthetase inhibiting activity.The NSAID component may be selected from phenylalkanoic acids, such asdiclofenac, flurbiprofen, ketorolac, bromfenac, piroxicam and the like;indoles, such as indomethacin and the like; diarylpyrazoles, such ascelecoxib and the like; pyrrolo pyrroles; and other agents that inhibitprostaglandin synthesis. A very useful NSAID component is the pyrrolopyrrole which has a propionic acid moiety, known as ketorolac andderivatives thereof, such as non-toxic esters and salts thereof. Pyrrolopyrroles have been suggested for use in the treatment of certainophthalmic diseases in Waterbury U.S. Pat. No. 4,454,151, the disclosureof which is incorporated in its entirety herein by reference.

The NSAID component may be present in the present compositions in anysuitable concentration effective to reduce inflammation or pain when thecomposition is placed in a mammalian eye. The NSAID component preferablyis present in an amount in a range of about 0.001% (w/v) or less toabout 10% (w/v) or more, and more preferably in a range of about 0.02%(w/v) to about 0.5% (w/v) or about 1% (w/v).

The antinflammatory activity of the NSAID may also be useful in thetreatment of inflammation caused by allergic and autoimmune disorders;in some of these disorders infection is not necessarily present. Inother inflammatory disorders pain is not presnt.

The present carrier components may be selected from pharmaceuticallyacceptable organic and/or inorganic components which, preferably, in thepresent compositions are ophthalmically acceptable. As used herein, theterm “ophthalmically acceptable” refers to a material which, at theconcentration or amount in question, is compatible with ocular tissue,that is the material does not cause significant or undue detrimentaleffects when brought into contact with ocular tissue. The carriercomponent preferably is ophthalmically acceptable. Preferably, eachcomponent of the present compositions is also compatible with the othercomponents of the compositions.

Examples of suitable materials useful in the present carrier componentsinclude water, mixtures of water and water-miscible solvents such aslower alkanols or aralkanols, vegetable oils, polyalkylene glycols,petroleum-based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl mirstate, otherconventionally employed pharmaceutically acceptable materials and thelike.

The carrier component may also include auxiliary substances such asemulsifiers, wetting agents, bodying agents, buffer components, acidsand/or bases, tonicity adjuster components, surfactant components,viscosity agents, lubricity components, preservative components, othermaterials useful in ophthalmic formulations and the like, including, butnot limited to, such substances which are conventionally used inophthalmic compositions.

Examples of optionally useful bodying agents include, but are notlimited to, various polyethylene glycols, carbowaxes, petroleum jellyand the like.

Suitable buffers include, but are not limited to, inorganic buffers suchas phosphate buffers, borate buffers and the like, and organic buffers,such as acetate buffers, citrate buffers, tromethamine and the like.

Tonicity adjusters optionally useful in the present compositionsinclude, but are not limited to, dextrose, potassium chloride and/orsodium chloride and the like, preferably sodium chloride.

Acids optionally useful in the present compositions include boric acid,hydrochloric acid, acetic acid, other acids which are ophthalmicallyacceptable in the concentrations used, and the like.

Bases which may be included in the present compositions include, but arenot limited to, sodium and/or potassium hydroxides, other alkali and/oralkaline earth metal hydroxides, organic bases, other bases which areophthalmically acceptable in the concentrations used, and the like.

The acid/bases/buffers preferably are included, if at all, to provideand/or maintain the present compositions at a pH in the physiologicallyacceptable range, more preferably in a range of about 4 to about 8.5,still more preferably about 6 to about 8, and especially about 6.8 toabout 8.

Surfactant components optionally useful in the compositions of thepresent invention include, but are not limited to, lipoproteindetergents that when present in the compositions reduce the surfacetension between the compositions and the eye (lacrimal) fluid.Preferably, nonionic surfactants are used.

Viscosity agents optionally useful in the compositions of the presentinvention include, but are not limited to, cellulose derivatives such ashydroxypropylmethyl cellulose, sodium carboxymethyl cellulose,hydroxyethyl cellulose, other viscosity inducing materials useful inophthalmic formulations, and the like.

Lubricating components optionally useful in compositions of the presentinvention include, but are not limited to, polyvinyl alcohol,polyvinylpyrrolidone, carbopol and the like.

Preservative components optionally useful in the compositions of thepresent invention include, but are not limited to, BAK,organo-mercurials, such as thimerosal and phenylmercuric acetate andnitrate, quaternary ammonium compounds, methyl and propyl parabens,benzl alcohol, phenylethanol and the like. Because of the fungistaticactivity of the quinolone components of the present compositions, theconcentration of the preservative component, if present at all, in thepresent compositions may be, and preferably is, reduced, more preferablyby at least about 10% or at least about 20%, relative to theconcentration of the preservative needed in a similar compositionincluding, in place of the presently useful quinolone component withfungistatic activity, an antibiotic component without such fungistaticactivity and still be effectively preserved, for example, adequatelypreserved to pass the applicable United States and/or Europeanpreservative efficacy tests.

The present compositions may include effective amounts of chelating orsequestering components, such as ethylene diamine tetraacetic acid(EDTA), citric acid, tartaric acid and the like.

Other optional excipients useful in the present compositions includestabilizing agents such as antioxidants, for example, alkali metalmetabisulfates, ascorbic acid and the like.

The carrier component may be in various forms. In one embodiment, thecarrier component comprises a liquid, and the composition may be asolution or a suspension. In either situation, the carrier may simplycontain water and one or more auxiliary components noted elsewhereherein.

The present compositions may be in any suitable form effective to beadministered to the eye. Such forms include solutions, suspensions,ointments, gels, solids and the like. An ointment may be considered as aform intermediate between a suspension and a gel. Each of these forms ofthe present compositions can be prepared using techniques and processingwhich are conventional and well known in the art.

In another embodiment, the carrier component may be in the form of aclear material which forms a semi-solid “gel” at human bodytemperatures. Various polymers, many of which are conventional and wellknown in the art, can be included in the carrier components to providethe present compositions in the form of gels. For example, a polymersystem including alkylene diamine tetra substituted with about 40% toabout 80% poly(oxyethylene) units and about 20% to about 60%poly(oxypropylene) units may be employed. The molecular weight of thepolymer used preferably is at least about 7,000 and can be as high asabout 50,000, more preferably in the range of about 7,000 to about30,000. The gel forming component, if any is present in an amounteffective to provide the composition in the form of a gel. For example,such gel forming component may be present in an amount in a range ofabout 10% or less to about 50% or more by weight of the total carriercomponent.

The compositions may also be in the form of solid inserts, for example asolid dosage form that is suitable for insertion into the cul-de-sac ofa mammalian eye. To this end, the composition components can be includedwith a non-bioerodible insert, for example, one which after dispensingthe active component or components remains essentially intact, or abio-erodible insert, for example, one that either is soluble in lacrimalfluids, or otherwise disintegrates.

A solid water soluble polymer may be employed in the carrier component.Such polymers include, for example, cellulose derivatives such asmethylcellulose, sodium carboxymethyl cellulose, or a hydroxy loweralkyl cellulose such as hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose and the like; acrylates such aspolyacrylic acid salts, ethyl acrylates, polyacrylamides, naturalproducts such as gelatin, alginates, pectins, tragacanth, daraya,chondrus, agar, acacia; the starch derivatives such as starch acetate,hydroxyethyl starch ethers, hydroxypropy starch, as well as othersynthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone,polyvinyl methyl ether, polyethylene oxide, neutralized carbopol andxanthan gum, mixtures thereof and the like.

The present compositions may be prepared using conventional techniques,for example, by formation of solutions, gels, suspensions, etc., usingwell known and conventional techniques. For a more detailed discussionof the preparation and administration of ophthalmic formulations seeRemingtons Pharmaceutical Sciences, 15 Ed., Pgs. 1489 to 1504 (1975)which is incorporated in its entirety herein by reference.

In general, the present methods for treating mammalian eyes compriseadministering to the mammalian eye a therapeutically effective amount ofthe present composition thereby providing an effective antibiotic in themammalian eye and reducing inflammation and/or pain in the mammalianeye.

Methods for treating corneal injuries, such as corneal ulcers, are alsoincluded within the scope of the present invention. Such methodscomprise administering to a mammalian, preferably human, eye having acorneal injury a therapeutically effective amount of a compositioncomprising a quinolone component in an amount effective as an antibioticin the mammalian eye and a NSAID component in an amount effective, incombination with the quinolone component, to provide a reduction in paincaused by the corneal injury. Such reduction in pain, together with theantibiotic effectiveness of the presently useful compositions reducesthe discomfort to the patient resulting from the corneal injury andfacilitates or promotes the healing of the injury. Corneal injuriesinclude, but are not limited to, abrasions, lacerations, scratches,surgical trauma, accidental or incidental trauma, bruises and the liketo the cornea which are infected or are likely to become infected whichcause pain to the mammal.

The present useful corneal injury-treating compositions preferablyinclude a carrier component in an amount effective to act as a carrierfor the quinolone component and the NSAID component in the presentlyuseful compositions.

The quinolone components, NSAID components and carrier components usefulin treating corneal injuries preferably are as described elsewhereherein. The presently useful compositions can be in any suitable formeffective to treat the corneal injury, preferably in a form as describedelsewhere herein.

Methods for treating ocular infections, such as corneal infections, arealso included within the scope of the present invention. Such infectionsare caused by the presence of one or more microbes or pathogens in or onthe eye in an amount or quantity to detrimentally affect the eye, forexample, causing irritation, inflammation, redness, pain, tissue damageand the like. Examples of such infections include, but are not limitedto, keratitis, such as bacterial keratitis, as well as bacterialconjunctivitis and the like infections. The present infection treatingmethods comprise administering to a mammalian, preferably human, eyehaving an infection caused by one or more microbes or pathogens atherapeutically effective amount of a composition comprising a quinolonecomponent in an amount effective as an antibiotic in the mammalian eyeand an effective amount of a NSAID component.

In one embodiment, the NSAID component is effective to reduce the timeneeded to eliminate the infection relative to identically administeringa similar composition without the NSAID component. In addition, oralternately, the administering step, and preferably the NSAID componentused in the administering step, is effective to at least inhibit the oneor more microbes or pathogens causing the infection from adhering to asurface of the eye. In a very useful embodiment, the administering step,and preferably the NSAID component used in the administering step, iseffective to at least inhibit, or even substantially prevent,colonization of the one or more microbes or pathogens in the eye.

The presently useful ocular infection-treating compositions preferablyinclude a carrier component in an amount effective to act as a carrierfor the quinolone component and the NSAID component in the presentlyuseful compositions.

The quinolone components, NSAID components and carrier components usefulin treating ocular infections preferably are as described elsewhereherein. The presently useful compositions can be in any suitable formeffective to treat the ocular infection, preferably in a form asdescribed elsewhere herein.

The present use methods may be considered to be curative and/orpreventative when applied, presurgically or immediately posttraumatically, that is before a microbial infection develops, or beforeinflammation and/or pain and/or infection is apparent. The present usemethods are effective to reduce the risk of the formation of suchinfections and to reduce the severity of any inflammation or pain whichmay develop.

The present methods of use, including the general methods of use, themethods of treating corneal ulcers and the methods of treating ocularinfections, may involve any suitable administration step or steps toprovide an effective amount of the composition to the mammalian eye.Such administering may include, but is not limited to, topicalapplication to the eye, instillation into the eye, placing an insertinto the cul-de-sac (space) between the eyeball and the eyelid and thelike. Other conventional methods of administering compositions to theeye may be employed provided that the compositions are administered soas to provide the benefits desired.

The dosage level of the composition depends, of course, on many factors,for example, the particular application involved, the particular activecomponents employed, the concentration of the active components in thecomposition, the severity of the infection/inflammation/pain/cornealulcer and the individual's response to the treatment. Such dosage can beeasily determined by routine and well known techniques to achieve thedesired results in the individual patient being treated.

The following non-limiting examples illustrate certain aspects of thepresent invention.

EXAMPLES 1 TO 11

A series of compositions, Compositions 1 to 11, are prepared by blendingvarious components together. These compositions have the followingchemical make-ups. Composition 1 Ofloxacin 0.6 w/v % NaCl 0.79 w/v % pH6.4 q.s. 100% Composition 2 Moxifloxacin 0.1 w/v % NaCl 0.79 w/v % pH6.4 q.s. 100% Composition 3 Ofloxacin 0.6 w/v % NaCl 0.3 w/v % EDTA 0.1wt % Boric Acid 1.0 w/v % pH 6.4 q.s. 100% Composition 4 Moxifloxacin0.1 w/v % NaCl 0.3 w/v % EDTA 0.1 w/v % Boric Acid 1.0 w/v % pH 6.4 q.s.100% Composition 5 Bromfenac 0.1 w/v % Ofloxacin 0.6 w/v % NaCl 0.79 w/v% pH 6.4 q.s. 100% Composition 6 Bromfenac 0.1 w/v % Ofloxacin 1.0 w/v %NaCl 0.79 w/v % pH 6.4 q.s. 100% Composition 7 Ketorolac 0.5 w/v %Moxifloxacin 0.5 w/v % NaCl 0.3 w/v % EDTA 0.1 w/v % Boric Acid 1.0 w/v% pH 6.4 q.s. 100% Composition 8 Bromfenac 0.1 w/v % Moxifloxacin 0.5w/v % NaCl 0.3 w/v % EDTA 0.1 w/v % Boric Acid 1.0 w/v % pH 6.4 q.s.100% Composition 9 Bromfenac 0.1 w/v % Ofloxacin 0.3 w/v % NaCl 0.79 w/v% BAK 0.005 w/v % L-Arginine 0.28 w/v % pH 6.4 q.s. 100% Composition 10Bromfenac 0.1 w/v % Moxifloxacin 0.3 w/v % NaCl 0.79 w/v % BAK 0.005 w/v% METHOCEL ® 0.1 w/v % CARBOPOL ® 0.2 w/v % pH 6.4 q.s. 100% Composition11 Bromfenac 0.3 w/v % BAK 0.005 w/v % METHOCEL ® 0.1 w/v % CARBOPOL ®0.225 w/v % glycerine 2.6 w/v % pH 6.5 q.s. 100%(1) Methyl cellulose(2) One of a series of polymers of 2-propenoic acid crosslinked withalkyl ethers of pentoerythritol.

An abbreviated preservative efficacy test of each of these compositionsis performed using S. aureus ATCC 6538 and A. niger ATCC 16404 as thetest organisms. The compositions are tested against Ph Eur-A/B and USPcriteria according to ARM T-005. Ten (10) milliliter of each compositionis challenged with approximately 10⁵ cfu/ml of the indicated testorganism. At the appropriate time intervals, the amount of bacterial andfungal survivors are assayed using Dey Engley broth (DE) as theneutralizer media. DE, along with filtration, is sufficient atneutralizing the antimicrobial agents in the compositions. One (1) ml ofeach sample is diluted into nine (9) ml of DE. One (1) of the 1:10dilution is filtered through a 0.45 μm filter and washed with 100 mlsaline/TWEENO 80. After washing the filter a second time with 100 ml ofa saline/TWEEN® 80 solution, the filtrate is placed onto a TSA plate forbacteria and SAB for fungi. The same procedure as stated above wasfollowed for composition 11 (which is in the form of a gel) except a1:100 dilution of the product is made prior to filtration (0.1 ml ofproduct is added to 10 ml DE).

A summary of the expected results of these preservative efficacy testsis as follows: Composition USP Ph Eur-A Ph Eur-B 1 PASS FAIL MarginalPASS 2 PASS FAIL FAIL 3 PASS FAIL Marginal PASS 4 PASS FAIL PASS 5 PASSFAIL FAIL 6 PASS FAIL FAIL 7 PASS PASS Marginal PASS 8 PASS FAIL PASS 9PASS PASS PASS 10 PASS PASS PASS 11 PASS PASS PASS

Expected results of the preservative efficacy tests are as follows: TestOrganism Compositions Inoculum level Test Interval 1 2 3 4 5 6 S. aureus6 hours 2 × 10⁵ 9 × 10⁴ 1 × 10⁵ 8 × 10⁴ 8 × 10⁴ 1 × 10⁵ ATTC 6538 24hours 7 × 10⁴ 3 × 10⁴ 6 × 10⁴ <10 8 × 10³ 2 × 10³ 4 × 10⁵ 7 days <10 <10<10 1 × 10¹ <10 <10 14 days <10 <10 <10 <10 <10 <10 28 days <10 <10 <10<10 <10 <10 A. niger 7 days 8 × 10⁴ 8 × 10⁴ 4 × 10³ 1 × 10³ 7 × 10⁴ 7 ×10⁴ ATCC 16404 14 days 2 × 10⁴ 3 × 10⁴ 2 × 10³ 1 × 10³ 9 × 10⁴ 9 × 10⁴ 1× 10⁵ 28 days 1 × 10⁴ 3 × 10⁴ 2 × 10³ 8 × 10² 2 × 10⁴ 1 × 10⁴ TestOrganism Compositions Inoculum level Test Interval 7 8 9 10 11 S. aureus6 hours 1 × 10⁵ 1 × 10⁵ <10 <10 <10 ATTC 6538 24 hours 3 × 10³ 1 × 10⁴<10 <10 <10 4 × 10⁵ 7 days <10 <10 <10 <10 <10 14 days <10 <10 <10 <10<10 28 days <10 <10 <10 <10 <10 A. niger 7 days 2 × 10⁴ 3 × 10³ 1 × 10¹<10 1 × 10¹ ATCC 16404 14 days 2 × 10⁴ 7 × 10³ <10 <10 <10 1 × 10⁵ 28days 4 × 10² 1 × 10² <10 <10 <1

All of the compositions are expected to very effectively pass the USPET.In particular, the fact that Compositions 1 to 8, which include nocomponent known to be effective as a preservative, pass the USPET is anunpredictable result, especially since prior art compositions prior tothe July 1999 priority date of this application which have included aquinolone, such as ofloxacin or doxifloxicin, have includedpreservatives, such as BAK. In addition, Compositions 1 to 8 havesufficient antifungal activity to prevent A. niger from increasing inpopulation. Thus, the quinolone included in these compositions hassufficient fungistatic activity to act as a preservative for thecomposition against A. niger contamination.

EXAMPLES 12 TO 23

A further series of compositions, Compositions 12 to 24, are prepared byblending various components together. These compositions have thefollowing chemical make-ups. Each composition included sufficient waterto total 100% by weight. EXAMPLE CONCENTRATION, NO. COMPOSITION w/v % 12Bromfenac 0.1 Ofloxacin 0.3 NaCl 0.79 pH 6.4 13 Bromfenac 0.1 Ofloxacin0.3 NaCl 0.30 EDTA 0.1 Boric Acid 1.0 pH 6.4 14 Bromfenac 0.1 Ofloxacin0.3 NaCl 0.79 BAK 0.005 pH 6.4 15 Bromfenac 0.5 Ofloxacin 0.3 NaCl 0.79pH 7.4 16 Ketorolac 0.1 Ofloxacin 0.3 NaCl 0.79 BAK 0.005 pH 7.6 17Bromfenac 0.1 Ofloxacin 0.3 NaCl 0.79 BAK 0.005 Octoxynol ⁽³⁾ 0.007 pH6.4 18 Bromfenac 0.1 Ofloxacin 0.3 NaCl 0.79 BAK 0.005 Octoxynol ⁽³⁾0.007 pH 7.6 19 Bromfenac 0.1 Ofloxacin 0.3 NaCl 0.79 BAK 0.005Cyclodextrin ⁽⁴⁾ 0.1 pH 6.4 20 Bromfenac 0.1 Ofloxacin 0.5 NaCl 0.79 BAK0.005 Cyclodextrin ⁽⁴⁾ 0.1 pH 7.6 21 Bromfenac 0.1 Ofloxacin 0.3 NaCl0.79 Purite ⁽⁵⁾ 0.007 pH 7.6 22 Bromfenac 0.1 Ofloxacin 0.3 NaCl 0.79Purite ⁽⁵⁾ 0.007 Octoxynol ⁽³⁾ 0.007 pH 7.6 23 Bromfenac 0.1 Ofloxacin0.3 NaCl 0.79 Purite ⁽⁵⁾ 0.007 Cyclodextrin ⁽⁴⁾ 0.1 pH 7.6⁽³⁾ Polyethylene glycol (mono octylphenyl) ether⁽⁴⁾ 7-sulfobutylether beta-cyclodextrin⁽⁵⁾ Stabilized chlorine dioxide

The samples are tested for preservative efficacy against Ph Eur-A/B andUSP criteria according to ARM T-005. Ten (10) milliliters of each sampleare challenged with approximately 10⁵ cfu/ml of test organism. The testorganisms include S. aureus ATCC 6538, P. aeruginosa ATCC 9027, E. coliATCC 8739, C. albicans ATCC 10231, and A. niger ATCC 16404. At theappropriate time intervals, the amount of bacterial and fungal survivorsare assayed using DE as the neutralizer media. DE, along withfiltration, is sufficient at neutralizing the antimicrobial agents inthe compositions. One (1) ml of each sample is diluted into 9 ml of DE.The whole 10 ml is filtered through a 0.45 um filter and washed with 100ml of phosphate buffered saline pH 5.4. After washing the filter asecond time with 100 ml phosphate buffered saline/TWEEN® 80, the filteris placed onto a blood agar plate for bacteria and SAB for fungi.

The anticipated results are summarized in the below table. SAMPLE ID USPPh Eur-A Ph Eur-B 12 PASS FAIL FAIL 13 PASS FAIL FAIL 14 PASS PASS PASS15 PASS FAIL FAIL 16 PASS PASS PASS 17 PASS PASS PASS 18 PASS PASS PASS19 PASS FAIL PASS 20 PASS PASS PASS 21 PASS FAIL FAIL 22 PASS FAIL FAIL23 PASS FAIL FAIL

Detailed anticipated results of the preservation efficacy tests onCompositions 12 to 17 are as follows: Test Organism Composition Inoculumlevel Test Interval 12 13 14 15 16 17 S. aureus 6 hours 2 × 10⁵ 2 × 10⁵4 3 × 10⁵ <10 1 ATTC 6538 24 hours 2 × 10⁵ 2 × 10⁵ <10 3 × 10⁵ <10 <10 5× 10⁵ 7 days <10 2 × 10¹ <10 <10 <10 <10 14 days <10 <10 <10 <10 <10 <1028 days <10 <10 <10 <10 <10 <10 P. aeruginosa 6 hours <10 <10 <10 <10<10 <10 ATCC 9027 24 hours <10 <10 <10 <10 <10 <10 3 × 10⁵ 7 days <10 2× 10¹ <10 <10 <10 <10 14 days <10 <10 <10 <10 <10 <10 28 days <10 <10<10 <10 <10 <10 E. coli 6 hours 6 × 10¹ 5 × 10¹ <10 5 × 10¹ <10 <10 ATCC8739 24 hours 5 × 10² <10 <10 <10 <10 <10 5 × 10⁵ 7 days <10 <10 <10 <10<10 <10 14 days <10 <10 <10 <10 <10 <10 28 days <10 <10 <10 <10 <10 <10C. albicans 7 days 1 × 10⁵ 2 × 10⁵ <10 3 × 10⁵ <10 <10 ATCC 10231 14days 1 × 10⁵ 2 × 10⁵ <10 1 × 10⁵ <10 <10 3 × 10⁵ 28 days 8 × 10⁴ 9 × 10⁴<10 9 × 10⁴ <10 <10 A. niger 7 days 6 × 10⁴ 6 × 10⁴ 3 × 10¹ 7 × 10⁴ <103 × 10¹ ATCC 16404 14 days 4 × 10⁴ 3 × 10⁴ 4 6 × 10⁴ 1 × 10² <10 1 × 10⁵28 days 3 × 10⁴ 3 × 10⁴ <10 4 × 10⁴ <10 <10

All of the Compositions pass the USPET. Compositions 12 and 15, includeno component known to be effective as a preservative. AlthoughCompositions 12 and 15 do not pass the European Preservative EfficacyTests, they do have sufficient antifungal activity to prevent C.albicans and A. niger from increasing in population. The quinolone,bromfenac, included in these compositions is expected to have sufficientfungistatic activity to act as a preservative for the compositionagainst C. albicans and A. niger contamination.

EXAMPLES 24 TO 41

Compositions 5 to 10 and 12 to 23 are each administered to a human eyewhich has been subjected to surgical trauma. Before administration, eacheye exhibits a degree of inflammation and is the source of a degree ofpain.

Each composition in the form of a solution is administered to the eye inan amount of about 1 to 2 drops per eye with the drops containing about25 to 50 micro liters. The drops are administered 3 to 4 times per day.Each composition in the form of a gel is administered by placing about50 to 100 microliters of the composition between the eyelid and theeyeball 3 to 4 times a day.

After a week of such administering, each of the eyes treated exhibits noinflammation and is not a source of pain. In addition, each of the eyeshas remained free of microbial infection.

EXAMPLES 42 TO 59

Compositions 5 to 10 and 12 to 23 are each administered to a human eyewhich has a corneal ulcer. Before administration, each eye is the sourceof a substantial degree of pain.

Each composition in the form of a solution is administered to the eye inan amount of about 1 to 2 drops per eye with the drops containing about25 to 50 micro liters. The drops are administered every 30 minutes. Eachcomposition in the form of a gel is administered by placing about 50 to100 micro liters. of the composition between the eyelid and the eyeballevery 30 minutes.

Within one day after the initial administering, the pain resulting fromeach of the corneal ulcers is substantially eliminated. After two weeksof such administering, each of the corneal ulcers has substantiallycompletely healed and no pain from the ulcer is experienced. Inaddition, each of the eyes has remained free of microbial infection.

EXAMPLES 60 TO 78

Compositions 5 to 10 and 12 to 23 are each administered to a human eyewhich has a corneal microbial infection.

Each composition in the form of a solution is administered to the eye inan amount of about 1 to 2 drops per eye with the drops containing about25 to 50 micro liters. The drops are administered every 30 minutes. Eachcomposition in the form of a gel is administered by placing about 50 to100 micro liters of the composition between the eyelid and the eyeballevery 30 minutes.

After a period of time, on the order of from about 4 days to about 14days after of such administering, each of the corneal microbialinfections has been substantially completely eliminated and no pain fromthe infection is experienced. Using such compositions to treat theseocular infections, a reduced time period of administering thecompositions is needed to substantially completely eliminate theinfection relative to similar compositions without the NSAID component,(ketorolac or doxifloxacin). The NSAID component is believed to inhibitthe colonization of the microbes or pathogens causing the ocularinfections. For example, the NSAID component in the compositionadministered may inhibit or substantially prevent the offending microbesor pathogens from adhering to one or more surfaces of the eye, therebyinhibiting the spread or progress of the infection. The infection isresolved or eliminated more quickly using the present quinolone andNSAID-containing compositions relative to using similar compositionswithout the NSAID component.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced within thescope of the following claims.

1. A composition comprising: a quinolone component in an amounteffective as an antibiotic when the composition is placed in a mammalianeye; a bromofenac component in an amount effective to reduceinflammation or pain when the composition is placed in a mammalian eye;and a carrier component in an amount effective to act as a carrier forthe quinolone component and the bromfenac component in the composition,the carrier component being ophthalmically acceptable.
 2. Thecomposition of claim 1 wherein the quinolone component is an ofloxacincomponent.
 3. The composition of claim 1 wherein the quinolone componentis a doxifloxacin component.
 4. A sealed container comprising atherapeutically effective dose of a composition comprising a bromfenaccomponent in an amount effective as an antibiotic when the compositionis placed in a mammalian eye; a NSAID component in an amount effectiveto reduce inflammation or pain when the composition is placed in amammalian eye; and a carrier component in an amount effective to act asa carrier for the bromfenac component and the NSAID component in thecomposition, the carrier component being ophthalmically acceptable. 5.The container of claim 1 wherein the quinolone component is an ofloxacincomponent.
 6. The container of claim 1 wherein the quinolone componentis a doxifloxacin component.
 7. A method for treating a mammalian eyecomprising: administering to the mammalian eye a therapeuticallyeffective amount of the composition of claim 1, thereby providing aneffective antibiotic in the mammalian eye and reducing inflammation orpain in the mammalian eye.
 8. A method for treating a mammalian eyecomprising: administering to the mammalian eye a therapeuticallyeffective amount of the composition of claim 4, thereby providing aneffective antibiotic in the mammalian eye and reducing inflammation orpain in the mammalian eye.
 9. A method for reducing pain in a mammalianeye comprising: administering to a mammalian eye in need of painreduction a therapeutically effective amount of a composition comprisinga quinolone component in an amount effective as an antibiotic in themammalian eye and a bromfenac component in an amount effective, incombination with the quinolone component, to provide a reduction in painto the mammalian eye.
 10. The method of claim 7 wherein the quinolonecomponent is an ofloxacin component.
 11. The method of claim 7 whereinthe quinolone component is an doxifloxacin component.
 12. A method fortreating a corneal injury comprising: administering to a mammalian eyehaving a corneal injury a therapeutically effective amount of acomposition comprising a bromfenac component in an amount effective asan antibiotic in the mammalian eye and a NSAID component in an amounteffective, in combination with the quinolone component, to provide areduction in paid caused by the corneal injury.
 13. The method of claim12 wherein the quinolone component is an ofloxacin component.
 14. Themethod of claim 12 wherein the quinolone component is an doxifloxacincomponent.
 15. The method of claim 12 wherein the corneal injury is acorneal ulcer.
 16. A method for treating an ocular infection comprising:administering to a mammalian eye having an infection caused by one ormore pathogens a therapeutically effective amount of a compositioncomprising a quinolone component in an amount effective as an antibioticin the mammalian eye and a bromfenac component in an amount effective toreduce the time needed to eliminate the infection relative toidentically administering a similar composition without the NSAIDcomponent.
 17. The method of claim 16 wherein the administering step iseffective to inhibit colonization of the one or more pathogens in themammalian eye.
 18. The method of claim 17 wherein the mammalian eyeincludes a surface and the administering step is effective to at leastinhibit the one or more pathogens from adhering to the surface.
 19. Themethod of claim 17 wherein the ocular infection is a corneal infection.20. The method of claim 18 wherein the administering step is effectiveto inhibit colonization of the one or more pathogens in the mammalianeye.
 21. The method of claim 14 wherein the administering step iseffective to at least inhibit the one or more pathogens from adhering toa cornea of the eye.
 22. The method of claim 11 herein the quinolonecomponent is an ofloxacin halogenated quinolone component.
 23. Themethod of claim 11 wherein the quinolone component is a doxifloxacincomponent.
 24. A method for treating an ocular infection comprising:administering to a mammalian eye having an infection caused by one ormore pathogens a therapeutically effective amount of a compositioncomprising a quinolone component in an amount effective as an antibioticin the mammalian eye and a bromfenac component in an amount effective toinhibit colonization of the one or more pathogens in the mammalian eye.25. The method of claim 24 wherein the administering step is effectiveto inhibit colonization of the one or more pathogens in the mammalianeye.
 26. The method of claim 24 wherein the mammalian eye includes asurface and the administering step is effective to at least inhibit theone or more pathogens from adhering to the surface.
 27. The method ofclaim 24 wherein the ocular infection is a corneal infection.
 28. Themethod of claim 24 wherein the administering step is effective to atleast inhibit the one or more pathogens from adhering to a cornea of theeye.
 29. The method of claim 24 herein the quinolone component is anofloxacin component.
 30. The method of claim 24 wherein the quinolonecomponent is a doxifloxacin component.